Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity. In aqueous solutions cyclodextrins are able to form inclusion complexes with many drugs by taking up a drug molecule, or more frequently some lipophilic moiety of the molecule, into the central cavity. This property has been utilized for drug formulation and drug delivery purposes. Formation of drug/cyclodextrin inclusion complexes, their effect on the physicochemical properties of drugs and usage in pharmaceutical products has been reviewed (Loftsson, Jarho et al. 2005). For a variety of reasons, including cost, formulation bulk and toxicology, the amount of cyclodextrin that can be included in drug formulations is limited. This is further complicated by the fact that the complexation efficacy of cyclodextrins is, in general, very low and their molecular weight is rather high. Previously it has been shown that complexation efficacy of cyclodextrins can be significantly enhanced by including small amount of a water-soluble polymer in the aqueous complexation medium (Thorsteinn Loftsson, Cyclodextrin complexation, European Patent No.: 0579435 (Mar. 17, 1999); Thorsteinn Loftsson, Cyclodextrin Complexation, U.S. Pat. No. 5,472,954 (Dec. 5, 1995); Thorsteinn Loftsson, Cyclodextrin complexation, European Patent No.: 0579435 (Mar. 17, 1999)). The polymers increase the apparent stability constant of the drug/cyclodextrin complexes through formation of ternary drug/cyclodextrin/polymer complexes. Thus, on the average 40 to 50% less CD is needed when a polymer is present. Furthermore, some studies have shown that drug bioavailability from formulations containing a ternary drug/cyclodextrin/polymer complex is greater than from a comparable drug/cyclodextrin binary complex. In general, the water-soluble polymers improve both pharmaceutical and biological properties of drug/cyclodextrin complexes. Until recently it was generally believed that most drugs form simple 1:1 or 1:2 drug/cyclodextrin inclusion complexes. However recently it has been shown that cyclodextrins and cyclodextrin complexes self-associate to form aggregates and that those aggregates can act as solubilizers themselves (Mele, Mendichi et al. 1998; González-Gaitano, Rodríguez et al. 2002; Magnusdottir, Másson et al. 2002; Loftsson, Másson et al. 2004). There are some indications that the water-soluble polymers and certain organic and inorganic salts enhance the complexation efficiency by stabilizing these aggregates by forming non-inclusion complexes (Loftsson, Matthíasson et al. 2003; Loftsson and Másson 2004; Loftsson, Másson et al. 2004; Duan, Zhao et al. 2005; Loftsson, Össurardóttir et al. 2005). The critical cyclodextrin concentration of the aggregate formation is about 5.4% (w/v) (Duan, Zhao et al. 2005; Loftsson, Össurardóttir et al. 2005). Lysine, polyvinylpyrrolidone and magnesium ions formed non-inclusion complexes resulting in formation of ternary, quaternary and even pentenary complexes in aqueous solutions (Duan, Zhao et al. 2005). The diameter of these self-assembling aggregates has been estimated to be about 6 nm (aggregates of two or three drug/cyclodextrin complexes).
The usage of cyclodextrins in ophthalmic formulation has been reviewed (Loftsson and Järvinen 1999; Loftsson and Stefánsson 2002). Cyclodextrins make it possible to formulate lipophilic drugs in aqueous eye drop solutions. This may be useful for the formulation of a variety of lipophilic drugs that have not been available as eye drops or only in suboptimal formulations. Steroid drugs, including corticosteroids, are a good example of such drugs. They are lipophilic and have only been available in eye drops as prodrugs or suspensions with limited concentration and bioavailability. Likewise, carbonic anhydrase inhibitors have only been available as oral formulation or aqueous eye drop formulation where the pH has to be adjusted to non-physiological values. With cyclodextrins it is possible to increase the concentration of dissolved drug and enhance drug bioavailability and create formulations that offer more effective and less frequent treatment schedules.
Drug elimination from pre-corneal area. After ocular instillation, aqueous eye drops will mix with the tear fluid and be dispersed over the eye surface. However, various pre-corneal factors will limit the ocular absorption by shortening corneal contact time of applied drugs. The most important factors are the drainage of installed solution, non-corneal absorption and induced lacrimation. These factors, and the corneal barrier itself, will limit penetration of a topically administered ophthalmic drug. As a result, only few percentages of the applied dose are delivered into the intraocular tissues. The major part (50-100%) of the administered dose will be absorbed into the systemic drug circulation which can cause various side effects. Following instillation of an applied eye-drop (25-50 μl) onto the pre-corneal area of the eye, the greater part of the drug solution is rapidly drained from the eye surface and the solution volume returns to the normal resident tear volume of about 7 μl. Thereafter, the pre-ocular solution volume remains constant, but drug concentration decreases due to dilution by tear turnover and corneal and non-corneal absorption. The value of the first-order rate constant for the drainage of eye drops from pre-corneal area is typically about 1.5 min−1 in humans. Normal tear turnover is about 1.2 μl/min in humans (Sugrue 1989). The precorneal half-life of topically applied drugs is between 1 and 3 minutes.
Drug delivery to the posterior segments of the eye. Drug delivery to the posterior part of the eye (e.g. to retina, choroid, vitreous and optic nerve) is important for treating several disorders such as age-related macular degeneration, diabetic retinopathy, retinal venous occlusions, retinal arterial occlusion, macular edema, postoperative inflammation, uveitis retinitis, proliferative vitreoretinopathy and glaucoma. Due to anatomic membrane barriers (i.e. cornea, conjunctiva and sclera) and the lachrymal drainage it can be quite challenging to obtain therapeutic drug concentrations in the posterior parts of the eye after topical drug administration. Reaching the posterior part of the eye is even more challenging task because of the anatomical and physiological barriers associated with this part of the eye. Since those barriers cannot be altered with non-invasive methods, the ophthalmic formulations have to be improved in some way to increase the ocular bioavailability. To date, there is no noninvasive, safe and patient-friendly drug delivery system that is specific and effective for the posterior part of the eye. In general, drugs can enter the eye via three distinctive routes, i.e. a) through conjunctiva/sclera after topical application, b) from the anterior part after topical application, and c) from the systemic circulation after topical application, parenteral, oral, and intranasal or other administration route that delivers drug to the blood circulation. Then drugs can be delivered to the eye via invasive methods such as direct drug injection into the vitreous humor or subconjunctival injections. Invasive methods can cause discomfort for the patient and can also lead to complications that are even more serious than the disease being treated. In most cases, topical or systemic administration is used to treat posterior diseases despite limited bioavailability from these formulations.
It is generally accepted that eye drops are ineffective and of little benefit in delivering drugs in therapeutic concentrations to the posterior segment of the eye (Myles et al 2005; Raghava et al 2004; Yasukawa et al 2005). Therefore various approaches have been developed where drugs are injected into the vitreous cavity (Jonas 2005), injected under the conjunctiva or tenon's capsule and various devices invented that may be introduced into the eye (Yasukawa et al 2005). All of these approaches are based on the premise that non-invasive topical methods to effectively deliver drugs, such as corticosteroids, to the posterior segment of the eye are not available, and invasive methods are the only alternative (Myles et al 2005; Raghava et al 2004; Yasukawa et al 2005; Beeley et al 2005).
Microspheres and nanoparticles are colloidal drug carriers in the micro- and submicron range. These systems were developed to overcome solubility problems of poorly soluble drugs as well as for long acting injectable depot formulations and specific drug targeting options. These carriers (without cyclodextrin) were also evaluated for ophthalmic drug delivery purposes over the past 25 years (Zimmer and Kreuter 1995). Nanoparticles formed by surface active cyclodextrin derivatives have been studied but not specifically for topical drug delivery to the eye. Previously, aqueous eye drop suspensions have been studied but in these studies the particles were obtained by including insufficient amounts of cyclodextrin to the formulations, that is the solid particles consisted of relatively pure drug and not drug/cyclodextrin complexes (H. O. Ammar, S. A. El-Nahhas and R. M. Khalil, Cyclodextrins in acetazolamide eye drop formulations, Pharmazie, 53, 559-562 (1998); T. Loftsson, H. Fririksdóttir, E. Stefánsson, S. Thórisdóttir, Ö. Gumundsson, and T. Sigthórsson, Topically effective ocular hypotensive acetazolamide and ethoxyzolamide formulations in rabbits, J. Pharm. Pharmacol., 46, 503-504 (1994)). In this present invention the parent α-, β- and γ-cyclodextrin, and their currently acceptable derivatives for pharmaceutical products, are used to form drug containing particles for ophthalmic drug delivery.